Process for preparing resorcinol derivatives

ABSTRACT

The present invention relates to an improved process for preparing 4-substituted resorcinol derivatives, and intermediate compounds useful in the preparation of such resorcinol derivatives.

This application claims priority from U.S. provisional application Ser.No. 60/189,704, filed Mar. 15, 2000.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparing4-substituted resorcinol derivatives.

BACKGROUND OF THE INVENTION

Resorcinol derivatives are known to be useful for a variety of purposes.For example, in the cosmetic field, resorcinol derivatives have beenused as skin lightening agents. The use of resorcinol derivatives asskin lightening agents is described in European Patent Application EP904,774, published Mar. 31, 1999; U.S. Pat. No. 5,468,472, issued Nov.21, 1995; U.S. Pat. No. 5,399,785, issued Mar. 21, 1995; European PatentApplication EP 623,339, published Nov. 9, 1994; JP 5-4905, publishedJan. 14, 1993; and European Patent Application EP 341,664, publishedNov. 15, 1989.

Resorcinol derivatives have also been used as dandruff control agents(JP 4-169516, published Jun. 17, 1992); as anti-acne agents (JP4-169511, published Jun. 17, 1992); as potentiators of anti-microbialcompounds (U.S. Pat. No. 4,474,748, issued Oct. 2, 1984); asanti-browning agents for foods (U.S. Pat. No. 5,304,679, issued Apr. 19,1994); and in the preparation of photographic dye images (U.S. Pat. No.3,756, 818, issued Sep. 4, 1973).

The present invention provides an improved process for preparing4-substituted resorcinol derivatives. The present invention furtherprovides intermediate compounds useful in preparing such resorcinolderivatives, as well as processes for preparing the intermediatecompounds. The improved process of the present invention is easier touse than standard methods for preparing resorcinol derivatives in largequantities. In addition, the improved process of the present inventionresults in a higher yield of final product than standard methods.

SUMMARY OF INVENTION

The invention provides a process for preparing a resorcinol derivativeof formula I:

or a pharmaceutically acceptable salt thereof, wherein the dashed lineindicates an optional double bond at that position, and wherein X and Yare each independently selected from hydrogen, (C₁-C₁₂)alkyl,(C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, or X and Y are taken together with thecarbon to which they are attached to form a (C₄-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring, provided that the (C₄-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring is not aromatic; which (C₁-C₁₂)alkyl,(C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, (C₄-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring is optionally substituted by one to threeindependently selected groups Z, wherein Z is any substituent capable ofbeing substituted thereon where the process of the present invention canbe used to prepare the particular substituted resorcinol derivative.

In a preferred embodiment, Z is selected from the group consisting ofcyano; halo; (C₁-C₆)alkyl; aryl; (C₂-C₉)heterocycloalkyl;(C₂-C₉)heteroaryl; aryl(C₁-C₆)alkyl-; ═O; ═CHO(C₁-C₆)alkyl; amino;hydroxy; (C₁-C₆)alkoxy; aryl(C₁-C₆)alkoxy-; (C₁-C₆)acyl;(C₁-C₆)alkylamino-; aryl(C₁-C₆)alkylamino-; amino(C₁-C₆)alkyl-;(C₁-C₆)alkoxy-CO—NH—; (C₁-C₆)alkylamino-CO—; (C₂-C₆)alkenyl;(C₂-C₆)alkynyl; hydroxy(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)alkyl-;(C₁-C₆)acyloxy(C₁-C₆)alkyl-; nitro; cyano(C₁-C₆)alkyl-;halo(C₁-C₆)alkyl-; nitro(C₁-C₆)alkyl-; trifluoromethyl;trifluoromethyl(C₁-C₆)alkyl-; (C₁-C₆)acylamino-;(C₁-C₆)acylamino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)acylamino-;amino(C₁-C₆)acyl-; amino(C₁-C₆)acyl(C₁-C₆)alkyl-;(C₁-C₆)alkylamino(C₁-C₆)acyl-; ((C₁-C₆) alkyl)₂amino(C₁-C₆)acyl-;—CO₂R²; —(C₁-C₆)alkyl-CO₂R²; —C(O)N(R²)₂; —(C₁-C₆)alkyl-C(O)N(R²)₂;R²ON═; R²ON═(C₁-C₆)alkyl-; R²ON═CR²(C₁-C₆)alkyl-; —NR²(OR²);—(C₁-C₆)alkyl-NR²(OR²); —C(O)(NR²R²); —(C₁-C₆)alkyl-C(O)(NR²OR²);—S(O)_(m)R²; wherein each R² is independently selected from hydrogen,(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—, wherein R³ is(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—(C₁-C₆)alkyl-;R⁴R⁵N—C(O)—O—; R⁴R⁵NS(O)₂—; R⁴R⁵NS(O)₂(C₁-C₆)alkyl-; R⁴S(O)₂R⁵N—;R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein m is 0, 1 or 2, and R⁴ and R⁵ are eachindependently selected from hydrogen or (C₁-C₆)alkyl; —C(═NR⁶)(N(R⁴)₂);—(C₁-C₆)alkyl-C(═NR⁶)(N(R⁴)₂) wherein R⁶ represents OR² or R² wherein R²is defined as above; —OC(O)aryl(C₁-C₆)alkyl; —NH(C₁-C₆)alkyl;aryl(C₁-C₆)alkyl-HN—; and a ketal.

The present invention also provides various intermediate compoundsuseful in this process, and methods for making them. Specifically, thisinvention relates to a process for preparing a compound of formula (6)

wherein W is hydrogen or a protecting group;

wherein X and Y are each independently selected from hydrogen,(C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, or X and Y are takentogether with the carbon to which they are attached to form a(C₄-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, provided that the(C₄-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring is not aromatic; andwherein the (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl,(C₄-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring is optionally furthersubstituted by one to three independently selected groups Z, where Z isas defined above;

comprising reacting a compound of formula (5)

wherein Q is halo, with a base to form the compound of formula (6). In apreferred embodiment, Q is bromo, iodo or chloro; more preferably Q isbromo or iodo; and most preferably Q is bromo.

The present invention further provides a process for preparing acompound of formula

wherein W, X and Y are as defined above;

comprising reacting a compound of formula (5)

wherein Q is as defined above, with a base to form the compound offormula (7).

In a preferred embodiment, the compound of formula (5) is prepared byreacting the compound of formula (4)

wherein W, X and Y are as defined above, with a halogenating agent,wherein the halogen corresponds to Q in the compound of formula (5). Ina preferred embodiment, Q is bromo, and the compound of formula (5) isprepared by reacting the compound of formula (4) with a brominatingagent such as, e.g., N-bromosuccinimide.

In a further preferred embodiment, the compound of formula (4) isprepared by reacting a compound of formula (2)

with a compound of formula (3)

wherein W, X and Y are as defined above, in the presence of a base toform the compound of formula (4).

The present invention further provides a process for preparing acompound of formula

wherein Q, W, X and Y are as defined above, comprising reacting thecompound of formula (4)

with a halogenating agent, as described above, to form the compound offormula (5).

In a preferred embodiment, the compound of formula (4) is prepared byreacting a compound of formula (2)

with a compound of formula (3)

wherein W, X and Y are as defined above, in the presence of a base toform the compound of formula (4).

The present invention further provides a process for preparing acompound of formula

wherein W, X and Y are as defined above; comprising reacting a compoundof formula (2)

with a compound of formula (3)

in the presence of a base to form the compound of formula (4).

The present invention further provides a process for preparing acompound of formula I(a)

wherein X and Y are defined as above, comprising:

(a) reacting a compound of formula (5)

wherein Q is halo, W is hydrogen or a protecting group, and X and Y areas defined above, with a base to form a compound of formula (6); and

(b) where W is H, reducing the compound of formula (6) so formed to formthe compound of formula I(a); or

(c) where W is a protecting group, reducing the compound of formula (6)so formed and removing the protecting group to form the compound offormula I(a).

In a preferred embodiment, the compound of formula (6) is reduced toform the compound of formula I(a) by reaction with triethysilane in thepresence of a Lewis acid, or alternatively by hydrogenation understandard conditions.

The present invention further provides a process for preparing acompound of formula I(a)

wherein X and Y are as defined above; comprising:

(a) reacting a compound of formula (5)

wherein Q is halo, W is hydrogen or a protecting group, and X and Y areas defined above, with a base to form a compound of formula (7); and

(b) where W is H, hydrogenating the compound of formula (7) so formed toform the compound of formula I(a); or

(c) where W is a protecting group, hydrogenating the compound of formula(7) so formed and removing the protecting group to form the compound offormula I(a).

The present invention further provides a process for preparing acompound of formula I(a)

wherein X and Y are defined as above; comprising:

(a) reacting a compound of formula (5)

wherein Q is halo, W is hydrogen or a protecting group, and X and Y areas defined above, with a base to form a compound of formula (6);

(b) reacting the compound of formula (6) so formed with a base to form acompound of formula (7); and

(c) where W is H, hydrogenating the compound of formula (7) so formed toform the compound of formula I(a); or

(d) where W is a protecting group, hydrogenating the compound of formula(7) so formed and removing the protecting group to form the compound offormula I(a).

The present invention further provides a process for preparing acompound of formula I(a)

wherein X and Y are as defined above; comprising:

(a) reacting a compound of formula (5)

wherein Q is halo, W is hydrogen or a protecting group, and X and Y areas defined above, with a base to form a compound of formula (6);

(b) reacting the compound of formula (6) so formed with a base to form acompound of formula (7); and

(c) where W is H, hydrogenating the compound of formula (7) so formed toform the compound of formula I(a); or

d) where W is a protecting group, removing the protecting group fromcompound (7) so formed to form the compound of formula I(b)

and hydrogenating the compound of formula I(b) so formed to form thecompound of formula I(a).

The present invention further provides a process for preparing acompound of formula I(a)

wherein X and Y are as defined above; comprising:

(a) reacting a compound of formula (5)

wherein Q is halo, W is hydrogen or a protecting group, and X and Y areas defined above, with a base to form a compound of formula (7); and

(b) where W is H, hydrogenating the compound of formula (7) so formed toform the compound of formula I(a); or

(c) where W is a protecting group, removing the protecting group fromcompound (7) so formed to form the compound of formula I(b)

and hydrogenating the compound of formula I(b) so formed to form thecompound of formula I(a).

The present invention further comprises a process for preparing acompound of formula I(b)

wherein X and Y are as defined above; comprising:

(a) reacting a compound of formula (5)

wherein Q is halo, W is hydrogen or a protecting group, and X and Y areas defined above, with a base to form a compound of formula (6);

(b) reacting the compound of formula (6) so formed with a base to form acompound of formula I(b) when W is H, and a compound of formula (7) whenW is a protecting group; and

(c) when W is a protecting group, removing the protecting group from thecompound of formula (7) so formed to form the compound of formula I(b).

The present invention further provides a process for preparing acompound of formula I(b)

wherein X and Y are defined as above; comprising:

(a) reacting a compound of formula (5)

wherein Q is halo, W is hydrogen or a protecting group, and X and Y areas defined above, with a base to form a compound of formula I(b) when Wis H, and a compound of formula (7) when W is a protecting group; and

(b) when W is a protecting group, removing the protecting group from thecompound of formula (7) so formed to form the compound of formula I(b).

As explained below in the description of Scheme I, where W is H, thecompound of formula (5) can exist in equilibrium with the compound offormula (5′) as follows.

where W is H, the compound of formula (5′) may be formed directly fromthe compound of formula (4). In all of the processes described hereinwhere W is H, where the compound of claim (5) is utilized, the compoundof claim (5′) can be utilized in its place under the same reactionconditions as recited, e.g., to prepare the compounds of formula (6) or(7). The present invention also provides a process for preparing thecompound of formula (5′) by treating the compound of formula (4), whereW is H, with a halogenating agent to form the compound of formula (5′).

The various processes of the present invention, as described above, areincorporated into Scheme 1, shown below.

In a preferred non-limiting embodiment, X and Y are taken together withthe carbon to which they are attached to form a (C₅-C₈)cycloalkyl ringor a (C₅-C₈)cycloalkenyl ring having the following structure:

wherein n is 0, 1, 2 or 3, where such (C₅-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring is optionally substituted, and wherein thedashed line indicates an optional double bond at that position. In anon-limiting embodiment, the (C₅-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring is substituted by one to three independentlyselected groups Z as defined above.

In a preferred embodiment, X and Y are taken together with the carbon towhich they are attached to form a cyclohexyl or cyclohexenyl ring, andmost preferably a cyclohexyl ring.

In a further preferred embodiment, X and Y are taken together with thecarbon to which they are attached to form a cyclopentyl or cyclopentenylring, and most preferably a cyclopentyl ring.

In a further preferred embodiment, the (C₅-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring is not substituted.

In a further preferred embodiment, the (C₅-C₈)cycloalkyl ring or(C₁-C₈)cycloalkenyl ring is monosubstituted. More preferably, X and Yare taken together with the carbon to which they are attached to form amonosubstituted cyclohexyl or monosubstituted cyclopentyl ring.

In a further preferred embodiment, the (C₅-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring is disubstituted. More preferably, X and Y aretaken together with the carbon to which they are attached to form adisubstituted cyclohexyl or disubstituted cyclopentyl ring.

Where X and Y are taken together with the carbon to which they areattached to form a cyclohexyl or cyclohexenyl ring, the ring ispreferably substituted at the 3- or 4-position, and more preferably atthe 4-position.

Where X and Y are taken together with the carbon to which they areattached to form a cyclopentyl or cyclopentenyl ring, the ring ispreferably substituted at the 3-position.

In a further preferred embodiment, X and Y are taken together with thecarbon to which they are attached to form:

which is substituted with one to three independently selected groups Zas described above;

wherein n is 0, 1, or 2.

In a further preferred embodiment, n is 0 or 1.

In a further preferred embodiment, n is 0; and the dashed linerepresents a double bond at that position.

In a further preferred embodiment, n is 1.

In a further preferred embodiment, the ring formed by X and Y takentogether with the carbon to which they are attached is substituted byOH, ═O, ═NOH, CH₂OH or

or a combination thereof.

In a further preferred embodiment, n is 0; the ring formed by X and Ytaken together with the carbon to which they are attached is substitutedby ═NOH; and the dashed line represents a double bond at that position.

In a further preferred embodiment, n is 1; and the ring formed by X andY taken together with the carbon to which they are attached issubstituted by OH, ═O, ═NOH, CH₂OH, or

or a combination thereof.

Where Z is a (C₂-C₉)heterocycloalkyl substituent, it is preferably agroup of the formula:

wherein m is 0, 1 or 2, and

Q is CH₂, NR², O, S, SO, or SO₂.

In a further preferred embodiment, X and Y are taken together with thecarbon to which they are attached to form a cyclohexyl, cyclohexenyl,cyclopentyl or cyclopentenyl ring that is monosubstituted with Zselected from the group consisting of OH, R³C(O)O—,R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R²ON═(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-;—NR²(OR²), R⁴S(O)₂R⁵N—-, and R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein R², R³, R⁴and R⁵ are as defined above.

In a further preferred embodiment, X and Y are taken together with thecarbon to which they are attached to form a cyclohexyl or cyclopentylring that is monosubstituted with Z selected from the group consistingof OH, R³C(O)O—, R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R²ON═(C₁-C₆)alkyl-,R²ON═CR²(C₁-C₆)alkyl-, —NR²(OR²), R⁴S(O)₂R⁵N—, andR⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein R², R³, R⁴ and R⁵ are as defined above.

In a further preferred embodiment, Z is OH.

In a further preferred embodiment, Z is R³C(O)O—.

In a further preferred embodiment, Z is R³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, Z is R²ON═, R²ON═(C₁-C₆)alkyl-, orR²ON═CR²(C₁-C₆)alkyl-.

In a further preferred embodiment, Z is R²ON═.

In a further preferred embodiment, Z is —NR²(OR²).

In a further preferred embodiment, Z is R⁴S(O)₂R⁵N—.

In a further preferred embodiment, Z is R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a non-limiting embodiment, the process of the present invention canbe used to prepare a compound selected from the group consisting of:

4-cyclohexyl resorcinol;

4-cyclopentyl resorcinol;

4-(2,4-dihydroxyphenyl)cyclohexanol;

4-(2,4-Dihydroxyphenyl)cyclohexanone;

4-(2,4-Dihydroxyphenyl)cyclohexanone oxime;

O-Methyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

O-Benzyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

3-(2,4-dihydroxyphenyl)-2-cyclohexen-1-one;

(±)-3-(2,4-Dihydroxyphenyl )cyclohexanone;

3-(2,4-Dihydroxyphenyl )-2-cyclohexen-1-one oxime;

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone oxime;

(±)-4-[3-(1-Piperazinyl)cyclohexyl]-1,3-benzenediol;

(±)-N-[3-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

(±)-4-[3-(Hydroxymethyl)cyclohexyl]-1,3-benzenediol;

(±)-4-[3-(Hydroxyamino)cyclohexyl]-1,3-benzenediol;

cis/trans-4-[4-(Hydroxymethyl)cyclohexyl]-1,3-benzenediol;

cis/trans4-(4-Hydroxy4-methylcyclohexyl)-1,3-benzenediol;

(±)-O-Methyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

(±)-3-(2,4-Dihydroxyphenyl)-1-methylcyclohexanol;

(±)-O-Benzyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

3-(2,4-Dihydroxyphenyl)-2-cyclopentenone oxime;

(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone;

(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone oxime;

4-(2,4- Dihydroxyphenyl)-3-cyclohexen-1-one;

cis/trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetamide;

cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-butanesulfonamide;

trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

4-[4-(4-Hydroxyphenyl)cyclohexyl]-1,3-benzenediol;

cis/trans-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

trans-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

cis-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic acid;

cis-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic acid;

cis/trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic acid;

cis/trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetonitrile;

cis/trans-4-[4-(2-Aminoethyl)cyclohexyl]-1,3-benzenediol;

(±)-4-(3,3-Difluorocyclohexyl)-1,3-benzenediol;

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanecarboxamide;

(±)-3-(2,4-Dihydroxyphenyl)-N-hydroxycyclohexanecarboxamide;

(±)-3-(2,4-Dihydroxyphenyl)-N-ethylcyclohexanecarboxamide;

(±)-4-[3-Hydroxy-3-(hydroxymethyl)cyclohexyl]-1,3-benzenediol;

(±)-N-[3-(2,4-dihydroxyphenyl)cyclohexyl]acetamide;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl)-4-(dimethylamino)benzoate;

cis/trans-4-(2,4-Dihydroxyphenyl)cyclohexanecarboxylic acid;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethylcarbamate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl cyclohexylcarbamate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-tert-butylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-fluorobenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4- trifluoromethylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4- methoxybenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4- methylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4- chlorobenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dimethylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dichlorobenzoate;

trans4-[4-(Phenylsulfanyl)cyclohexyl]-1,3-benzenediol;

trans-4-[4-(Phenylsulfonyl)cyclohexyl]-1,3-benzenediol;

[4-(2,4-Dihydroxyphenyl)cyclohexyl]methyl propionate;

ethyl 4-(2,4-dihydroxyphenyl)-1-hydroxycyclohexane carboxylate;

cis/trans-4-[4-(hydroxyamino)cyclohexyl]-1,3-benzenediol;

trans-4-[4-(methoxyamino)cyclohexyl]-1,3-benzenediol;

and a pharmaceutically acceptable salt thereof.

The term “resorcinol derivative”, as used herein, refers to a compoundcomprising a resorcinol ring monosubstituted at the 4-position, asdefined above, and is represented by the structure of formula I.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof, which may or may not be furthersubstituted. Any substituents or functional groups on the alkyl group,as indicated herein, can be substituted anywhere on the alkyl groupwhere such substitutions are possible.

The term “aryl”, as used herein, refers to phenyl or naphthyl optionallysubstituted with one or more substituents, preferably from zero to twosubstituents, independently selected from halogen, OH, (C₁-C₆)alkyl,(C₁-C₆) alkoxy, amino, (C₁-C₆)alkylamino, di-((C₁-C₆)alkyl))amino,nitro, cyano and trifluoromethyl. Any substituents or functional groupson the aryl group, as indicated herein, can be substituted anywhere onthe aryl group.

The term “one or more substituents”, as used herein, refers to a numberof substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites.

The “halo”, as used herein, refers to halogen and, unless otherwiseindicated, includes chloro, fluoro, bromo and iodo.

The term “acyl”, as used herein, unless otherwise indicated, includes aradical of the general formula RCO wherein R is alkyl, alkoxy, aryl,arylalkyl, or arylalkyloxy and the terms “alkyl” or “aryl” are asdefined above.

The term “acyloxy”, as used herein, includes O-acyl groups wherein“acyl” is as defined above.

(C₂-C₉)Heterocycloalkyl, when used herein, refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skillin the art will understand that the connection of said(C₂-C₉)heterocycloalkyl ring can be through a carbon atom or through anitrogen heteroatom where possible.

(C₂-C₉)Heteroaryl, when used herein, refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, etc. One of ordinary skill inthe art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings can be through a carbon atom or through anitrogen heteroatom where possible.

Compounds of formula I may contain chiral centers and therefore mayexist in different enantiomeric and diastereomeric forms. This inventionrelates to preparation of all optical isomers, stereoisomers andtautomers of the compounds of formula I, and mixtures thereof.

Formula I, as defined above, also includes compounds identical to thosedepicted but for the fact that one or more hydrogen, carbon or otheratoms are replaced by isotopes thereof. Such compounds may be useful asresearch and diagnostic tools in metabolism pharmacokinetic studies andin binding assays.

The present invention also relates to preparation of thepharmaceutically acceptable acid addition and base addition salts of anyof the aforementioned compounds of formula I. The acids which are usedto prepare the pharmaceutically acceptable acid addition salts of theaforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The present invention also provides various intermediate compoundsuseful in the preparation of wide variety of resorcinol derivatives.

The present invention provides an intermediate compound of formula (4),where W, X and Y are as defined above.

In a preferred embodiment, the intermediate compound of formula (4) hasthe structure of formula (4a),

where W is as defined above, and n is 0, 1, 2 or 3.

In a further preferred embodiment, the intermediate compound of formula(4) has the structure of formula (4b) or (4c),

where W is as defined above.

In a further preferred embodiment, the intermediate compound of formula(4) has the structure of formula (4d),

where W and Z are as defined above, and n is 0, 1, 2 or 3.

In a further preferred embodiment, the intermediate compound of formula(4) has the structure of formula (4e) or (4f),

where W and Z are as defined above.

In a further preferred embodiment, the intermediate compound of formula(4) has the structure of formula (4g),

where W and each Z are as defined above, and n is 0, 1, 2 or 3.

In a further preferred embodiment, the intermediate compound of formula(4) has the structure of formula (4h) or (4i),

where W and each Z are as defined above.

The present invention further provides an intermediate compound offormula (5),

where Q, W, X and Y are as defined above.

In a preferred embodiment, the intermediate compound of formula (5) hasthe structure of formula (5a)

wherein Q and W are as defined above, and n is 0, 1, 2, or 3.

In a further preferred embodiment, the intermediate compound of formula(5) has the structure of formula (5b) or (5c)

wherein Q and W are as defined above.

In a further preferred embodiment, the intermediate compound of formula(5) has the structure of formula (5d)

wherein Q, W and Z are as defined above, and n is 0, 1, 2, or 3.

In a further preferred embodiment, the intermediate compound of formula(5) has the structure of formula (Se) or (5f),

where Q, W and Z are as defined above.

In a further preferred embodiment, the intermediate compound of formula(5) has the structure of formula (5g)

wherein Q, W and Z are as defined above, and n is 0, 1, 2, or 3.

In a further preferred embodiment, the intermediate compound of formula(5) has the structure of formula (5h) or (5i),

wherein Q, W and each Z are as defined above.

The present invention further provides an intermediate compound offormula (5′),

wherein Q, X and Y are as defined above.

In a preferred embodiment, the intermediate compound of formula (5′) hasthe structure of formula (5′a),

where Q is as defined above, and n is 0, 1, 2 or 3.

In a further preferred embodiment, the intermediate compound of formula(5′) has the structure of formula (5′b) or (5′c),

wherein Q is as defined above.

In a further preferred embodiment, the intermediate compound of formula(5′) has the structure of formula (5′d) or (5′e),

wherein Q and Z are as defined above.

In a further preferred embodiment, the intermediate compound of formula(5′) has the structure of formula (5′f) or (5′g),

wherein Q and each Z are as defined above.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention is described in the followingreaction schemes and discussion.

Referring to Scheme 1, compounds of formula (2) can be prepared startingwith compound (1), which is commercially available (Aldrich ChemicalCo.). A suitable protecting group can be selected as will be evident tothose of skill in the art. An example of a suitable protecting group isbenzyl. Conversion to compounds of formula (2) can occur under standardconditions. For instance, where the protecting group is benzyl,condensation can occur between compound (1) and benzyl alcohol with theremoval of water using Dean-Stark apparatus. Condensation of compoundsof formula (2) with compounds of formula (3) may occur using standardtechniques, for instance, treatment of compounds of formula (2) with abase, such as lithium diisopropylamide or lithium hexamethyldisilazide,in an ethereal solvent followed by the addition of a compound of formula(3) would give compounds of formula (4). When W is H, condensation ofcompounds of formula (2) with compounds of formula (3) requires the useof at least two equivalents of a suitable base such as lithiumdiisopropylamide in an suitable solvent such as tetrahydrofuran, with asuitable co-solvent such as hexamethylphosphoramide. Treatment ofcompounds of formula (4) with a suitable halogenating reagent such as,for example, N-bromosuccinimide in a chlorinated solvent, such asdichloromethane or chloroform, at about room temperature, can givecompounds of formula (5) where Q is halo, and preferably bromo. Where Wis H, the compound of formula (5) may exist in equilibrium with thecompound of formula (5′). Alternatively, where W is H, compounds offormula (5′) may be prepared directly from compounds of formula (4) bytreatment of the compound of formula (4) with a suitable halogenatingagent. The process of the present invention is intended to encompasseach of these various synthesis routes.

Compounds of formula (6) may then be generated from compounds of formula(5) or (5′) under suitable conditions. Such conditions may involvetreating compounds of formula (5) or (5′) with a base such as, e.g.,1,8-diazobicyclo[5.4.0]undec-7-ene in a suitable solvent such asN,N-dimethylformamide at about room temperature. Compounds of formulaI(a) may be generated using standard techniques, e.g., treatingcompounds of formula (6) with triethylsilane in the presence of a Lewisacid such as boron trifluoride in a chloronated solvent, followed bysuitable conditions to remove the protecting group, or hydrogenatingcompounds of formula (6) under standard conditions, would yieldcompounds of formula I(a). Compounds of formula (7) may be generatedfrom compounds of formula (5), (5′) or (6) under suitable reactionconditions. Such conditions may involve treating compounds of formula(5) or (5′) or (6) with a base such as, e.g.,1,8-diazobicyclo[5.4.0]undec-7-ene in a suitable solvent such asN,N-dimethylformamide at about 140° C. Other solvents such as toluene orN-methylpyrrolidinone may also be useful for this purpose. Subjection ofcompounds of formula (7) to standard hydrogenation conditions, e.g.,hydrogen gas and palladium on charcoal in ethanol, yields compounds ofthe general formula I(a) when the protecting group was benzyl. Where Wis a protecting group, compounds of formula I(b) can be formed bytreating compounds of formula (7) to standard conditions that will beobvious to those with skill in the art. Compounds of formula I(b) can inturn be converted to compounds of formula I(a) by standard hydrogenationconditions, such as described above. Compounds I(a) and I(b) fall withinthe scope of formula I.

Referring to Scheme 2 as an example of a more specific scheme, compoundsof formula (8) can be prepared starting with compound (1), which iscommercially available (Aldrich Chemical Co.). Conversion to compoundsof formula (8) can occur under standard conditions, for instance wherethe protecting group is benzyl, condensation can occur between compound(1) and benzyl alcohol with the removal of water using Dean-Starkapparatus. Condensation of compounds of formula (8) with compounds offormula (9) may occur using standard techniques, for instance, treatmentof compounds of formula (8) with a base such as lithium diisopropylamidein an ethereal solvent followed by the addition of a compound of formula(9) would give compounds of formula (10). Treatment of compounds offormula (10) with a suitable brominating reagent, such asN-bromosuccinimide in a chlorinated solvent at about room temperature,can give compounds of formula (11). Compounds of formula (12) may thenbe generated from compounds of formula (11) under suitable reactionconditions. Such conditions may involve treating compounds of formula(11) with a base such as 1,8-diazobicyclo[5.4.0]undec-7-ene in asuitable solvent such as N,N-dimethylformamide at about 140° C.Subjection of compounds of formula (12) to standard hydrogenationconditions, e.g., hydrogen gas and palladium on charcoal in anethanol/tetrahydrofuran mixture, yields compounds of the general formulaI(c) when the protecting group was benzyl. Compounds of formula I(d) maythen be obtained by subjecting compounds of formula I(c) to acidicconditions. Compounds of formulae I(c) and I(d) both fall within thescope of formula I.

It will be appreciated by those of skill in the art that in theprocesses described above, the functional groups of intermediatecompounds may need to be protected. The use of protecting groups iswell-known in the art, and is fully described, among other places, in:Protecting Groups in Organic Chemistry, J. W. F. McOmie, (ed.), 1973,Plenum Press; and in: Protecting Groups in Organic Synthesis, 2^(nd)edition, T. W. Greene & P. G. M. Wutz, 1991, Wiley-Interscience, whichare incorporated herein by reference in their entirety.

Resorcinol derivatives prepared according to the process describedherein are useful for all of the purposes previously described for thesetypes of compounds. For example, resorcinol derivatives useful asskin-lightening agents or for other cosmetic purposes can be preparedaccording to the process of the present invention.

Where resorcinol derivatives prepared according to the present inventionare useful as skin-lightening agents, these may be used to treatdisorders of human pigmentation, including solar and simple lentigines(including age/liver spots), melasma/chloasma and postinflammatoryhyperpigmentation. Such compounds reduce skin melanin levels byinhibiting the production of melanin, whether the latter is producedconstitutively or in response to UV irradiation (such as sun exposure),and typically by inhibition of the enzyme tyrosinase. Activeskin-lightening compounds prepared according to the present inventioncan be used to reduce skin melanin content in non-pathological states soas to induce a lighter skin tone, as desired by the user, or to preventmelanin accumulation in skin that has been exposed to UV irradiation.They can also be used in combination with skin peeling agents (includingglycolic acid or trichloroacetic acid face peels) to lighten skin toneand prevent repigmentation. The appropriate dose regimen, the amount ofeach dose administered, and specific intervals between doses of theactive compound will depend upon the particular active compoundemployed, the condition of the patient being treated, and the nature andseverity of the disorder or condition being treated. Preferably, theactive compound is administered in an amount and at an interval thatresults in the desired treatment of or improvement in the disorder orcondition being treated.

An active compound prepared according to the process of the presentinvention can also be used in combination with sun screens (UVA or UVBblockers) to prevent repigmentation, to protect against sun orUV-induced skin darkening or to enhance their ability to reduce skinmelanin and their skin bleaching action. An active compound preparedaccording the process of the present invention can also be used incombination with retinoic acid or its derivatives or any compounds thatinteract with retinoic acid receptors and accelerate or enhance theinvention's ability to reduce skin melanin and skin bleaching action, orenhance the invention's ability to prevent the accumulation of skinmelanin. An active compound prepared according to the present inventioncan also be used in combination with 4-hydroxyanisole.

The active compounds prepared according to the process of the presentinvention can also be used in combination with ascorbic acid, itsderivatives and ascorbic-acid based products (such as magnesiumascorbate) or other products with an anti-oxidant mechanism (such asresveratrol) which accelerate or enhance their ability to reduce skinmelanin and their skin bleaching action.

Skin-lightening active compounds prepared according to the presentinvention are generally administered in the form of pharmaceuticalcompositions comprising at least one of the compounds of formula (I),together with a pharmaceutically acceptable vehicle or diluent. Suchcompositions are generally formulated in a conventional manner utilizingsolid or liquid vehicles or diluents as appropriate for topicaladministration, in the form of solutions, gels, creams, jellies, pastes,lotions, ointments, salves, aerosols and the like.

Examples of vehicles for application of the active compounds of thisinvention include an aqueous or water-alcohol solution, an emulsion ofthe oil-in-water or water-in-oil type, an emulsified gel, or a two-phasesystem. Preferably, the compositions according to the invention are inthe form of lotions, creams, milks, gels, masks, microspheres ornanospheres, or vesicular dispersions. In the case of vesiculardispersions, the lipids of which the vesicles are made can be of theionic or nonionic type, or a mixture thereof.

In a skin-lightening composition comprising a resorcinol derivativeprepared according to the process of the present invention, theconcentration of the resorcinol derivative is generally between 0.01 and10%, preferably between 0.1 and 10%, relative to the total weight of thecomposition.

A skin-lightening resorcinol derivative prepared according to thepresent invention can be conveniently identified by its ability toinhibit the enzyme tyrosinase, as determined by any standard assay, suchas those described below.

1. Tyrosinase (DOPA Oxidase) Assay Using Cell Lysate:

Human melanoma cell line, SKMEL 188 (licensed from MemorialSloan-Kettering), is used in the cell lysate assay and the screen. Inthe assay, compounds and L-dihydroxyphenylalanine (L-DOPA) (100 μg/ml)are incubated with the cell lysates containing human tyrosinase for 8hrs before the plates are read at 405 nm. Potency of the compounds inDOPA oxidase assay is correlated very well with that in tyrosinehydroxylase assay using ³H-tyrosine as a substrate.

2. Melanin Assay in Human Primary Melanocytes:

Compounds are incubated with human primary melanocytes in the presenceof α-melanocyte stimulating hormone (α-MSH) for 2-3 days. Cells are thenlysed with sodium hydroxide and sodium dodecyl sulfate (SDS) and melaninsignals are read at 405 nm. Alternatively, ¹⁴C-DOPA is added to thecells in combination with tyrosinase inhibitors and acid-insoluble¹⁴C-melanin is quantitated by a scintillation counter. IC₅₀'s reflectthe inhibitory potency of the compounds in the new melanin synthesisthat was stimulated by α-MSH.

3. Tyrosine Kinase Assay (TK):

TK assays can be performed using purified tyrosine kinase domains ofc-met, erb-B2, or IGF-r. A specific antibody against phosphorylatedtyrosine residue is used in the assay. Colorimetric signals aregenerated by horseradish peroxidase, which is conjugated to theantibody.

4. Human Skin Equivalent Model:

A mixture of human melanocytes and keratinocytes is grown in anair-liquid interphase. This tissue culture forms a three dimensionalstructure that histologically and microscopically resembles the humanskin epidermis. Test compounds are added on top of the cells to mimictopical drug application. After incubation with the compounds (10 μM)for 3 days, the cells are washed extensively and lysed for DOPA oxidaseassay.

5. IL-1 Assay (Interleukin-1 Assay):

An IL-1α ELISA assay (R&D system) can be used to evaluate the effect ofcompounds on IL-1 secretion in a human skin equivalent model. IL-1α is apro-inflammatory cytokine and plays a role in UV-induced skininflammation.

6. In Vivo Study:

Black or dark brown guinea pigs with homogeneous skin color can be usedin this study. A solution of the test compound of formula 1 (5% inethanol:propylene glycol, 70:30) and the vehicle control are applied tothe animals twice daily, 5 days per week for 4-8 weeks. Using thisassay, depigmentation can be determined by subtracting the lightreflectance of untreated skin from the light reflectance of treatedskin.

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (400 MHz ¹H NMR) were measuredfor solutions in d₆DMSO, CDCl₃, or d₄-MeOH, and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane(TMS). The peak shapes are denoted as follows: s, singlet; d, doublet;t, triplet; q, quartet, m, multiplet, b, broad.

The following examples are illustrative only, and are not intended tolimit the scope of the present invention.

EXAMPLES Intermediate 1 3-(Benzyloxy)-2-cyclohexen-1-one

To a round bottomed flask equipped with magnetic stirrer and Dean Starkapparatus was added 1,3-cyclohexanedione (70.0 g, 624 mmol), toluene(500 ml), p-toluenesulfonic acid monohydrate (1.68 g, 8.83 mmol) andbenzyl alcohol (65.6 g, 606 mmol). The resulting solution was heatedunder reflux for 2 hr. The reaction mixture was cooled to roomtemperature and washed with saturated aqueous sodium carbonate solution(4×50 ml). The organic layer was washed with brine (50 ml), dried overmagnesium sulfate, filtered and concentrated in vacuo, affording a brownoil which crystallised upon standing. The crude crystalline material wasslurried in isopropyl ether (100 ml) and stirred at 0° C. for 2 hr. Themixture was filtered and the crystalline material was washed with icecold isopropyl ether (3×100 ml) followed by cold petroleum ether (100ml). The resulting solid was dried overnight under reduced pressure tofurnish the title compound (85.3 g, 68%). m/z (ES⁺) 203 (M+H⁺).

Intermediate 2(±)-3-(Benzyloxy)-6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-2-cyclohexen-1-one

To a round bottomed flask equipped with magnetic stirrer was addedanhydrous tetrahydrofuran (600 ml) and diisopropylamine (38.1 ml, 272mmol). The stirred solution was cooled to −78° C. and n-butyl lithium(113.4 ml, 272 mmol, 2.4 M in hexanes) was added dropwise via syringe in20 ml portions. The resulting yellow solution was stirred for 35 min at−78° C., then 3-(benzyloxy)-2-cyclohexen-1-one (50.0 g, 248 mmol) wasadded as a solution in anhydrous tetrahydrofuran (100 ml). The solutionwas stirred for 1 hr prior to the addition of cyclohexane-1,4-dionemonoethylene ketal (38.7 g, 248 mmol) as a solution in anhydroustetrahydrofuran (100 ml). The solution was stirred for 2 hr at −78° C.,then allowed to warm slowly to room temperature over 1 hr. Saturatedaqueous ammonium chloride (80 ml) was added, followed by dichloromethane(700 ml) and the mixture was stirred until no solids remained. Thelayers were separated and the aqueous phase extracted withdichloromethane (2×100 ml). The combined organic layers were washed withbrine (50 ml), dried over magnesium sulfate, then concentrated in vacuo.Trituration of the resulting solid with methanol afforded the titlecompound (78.4 g, 88%). m/z (ES⁺) 359 (M+H⁺).

Intermediate 3(±)-1-(Benzyloxy)-6-bromo-3-(1,4-dioxaspiro[4.5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one

A round bottomed flask equipped with magnetic stirrer was charged with(±)-3-(benzyloxy)-6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-2-cyclohexen-1-one(78.4 g, 219 mmol) and dichloromethane (600 ml). To the stirred solutionwas added N-bromosuccinimide (40.9 g, 230 mmol) in one portion, followedby aqueous hydrobromic acid (3 drops, 48% aqueous solution). Theresulting solution was stirred at room temperature for 2 hr, then pouredinto a separating funnel containing aqueous sodium metabisulfitesolution (150 ml) and dichloromethane (200 ml) and the funnel was shakenvigorously. The layers were separated and the organic layer was washedwith brine (200 ml), dried over magnesium sulfate, filtered, thenconcentrated in vacuo to give a solid. Trituration with methanol (500ml) afforded the title compound (82.8 g, 86%) as a white solid. m/z(ES⁺) 437 and 439 [(1:1), M+H⁺].

Intermediate 4 5-(Benzyloxy)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol

A round bottomed flask was charged with(±)-1-(benzyloxy)-6-bromo-3-(1,4-dioxaspiro[4.5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one(36 g, 82.4 mmol) anhydrous N, N-dimethylformamide (300 ml). To thestirred solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (13.6 ml,90.6 mmol) in one portion before heating to 140° C. for 19 hr withvigorous stirring. The reaction mixture was allowed to cool to roomtemperature and most of the solvent was removed under reduced pressure.The remaining oil was partitioned between dichloromethane (500 ml) andwater (100 ml), and the layers were separated. The organic phase waswashed with water (2×100 ml) followed by brine (100ml). The organicphase was dried over magnesium sulfate, filtered and concentrated invacuo to afford a brown solid which was adsorbed onto silica gel.Purification via flash column chromatography (SiO₂, dichloromethane thenethyl acetate/petroleum ether, 3:7, v/v) furnished an off white solidwhich was slurried in methanol (150 ml). The slurry was stirred for 20min, filtered and washed with methanol (50 ml). The title compound(18.2g, 65%) was isolated as a white solid after removal of excesssolvent under reduced pressure. m/z (ES⁺) 339(M+H⁺).

Example 1 4-(1,4-Dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol

A round bottomed flask equipped with magnetic stirrer was charged with5-(benzyloxy)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol (14.5 g, 42.8mmol) and tetrahydrofuran (50 ml). The stirred mixture was gently heateduntil a solution formed, after which the solution was allowed to cool toroom temperature. Ethanol (100 ml) and palladium (4.54 g, 10% onactivated carbon) were added sequentially. The reaction vessel was thenevacuated, placed under a hydrogen atmosphere and stirred vigorously for24 hr. The reaction mixture was filtered through a celite plug, washingwith ethyl acetate. The filtrate was concentrated in vacuo to give anoff white solid. The crude solid was slurried in dichloromethane (200ml), then collected on a sinter, affording the title compound (10.2 g,95%) as a white solid. m/z(ES⁺) 251(M+H⁺).

Example 2 4-(2,4-Dihydroxyphenyl)cyclohexanone

A round bottomed flask equipped with magnetic stirrer was charged with4-(1,4-dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol (11.3 g, 45.2 mmol),acetone (250 ml) and water (50 ml). To the stirred solution was addedpyridinium p-toluenesulfonate (1.14 g, 4.52 mmol) in one portion and thereaction mixture was then heated under reflux for 8 hr. After allowingthe reaction mixture to cool to room temperature, most of the acetonewas removed in vacuo and the remaining mixture was partitioned betweenethyl acetate (200 ml) and water (50 ml). The aqueous layer wasextracted with ethyl acetate (3×50 ml) and the combined organic layerswere washed with brine (30 ml), dried over magnesium sulfate, filteredand concentrated under reduced pressure to afford an off-white powder.After washing the powder with dichloromethane (100 ml) and removal ofexcess solvent under reduced pressure, the title compound (9.30 g, 100%)was obtained as an off-white powder. m/z (ES⁺) 207 (M+H⁺); δ_(H)(CD₃OD)1.84-1.97 (2H, m), 2.15-2.23 (2H, m), 2.36-2.45 (2H, m), 2.58-2.68 (2H,m), 3.39 (1H, tt), 6.26 (1H, dd), 6.34 (1H, d), 6.96 (1H, d).

All patents, patent applications, and publications cited above areincorporated herein by reference in their entirety.

The present invention is not to be limited in scope by the specificembodiments described herein, which are intended as single illustrationsof individual aspects of the invention, and functionally equivalentmethods and components are within the scope of the invention. Indeed,various modifications of the invention, in addition to those shown anddescribed herein will become apparent to those skilled in the art fromthe foregoing description. Such modifications are intended to fallwithin the scope of the appended claims.

What is claimed is:
 1. A compound having the structure of formula (5),

wherein Q is halo; wherein W is hydrogen or a protecting group; andwherein X and Y are each independently selected from hydrogen,(C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, or X and Y are takentogether with the carbon to which they are attached to form a(C₄-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, provided that the(C₄-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring is not aromatic; andwherein the (C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl,(C₄-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring is optionallysubstituted by one to three independently selected groups Z, where Z isselected from the group consisting of cyano; halo; (C₁-C₆)alkyl; aryl;(C₂-C₉)heterocycloalkyl; (C₂-C₉)heteroaryl; aryl(C₁-C₆)alkyl-; ═O;═CHO(C₁-C₆)alkyl; amino; hydroxy; (C₁-C₆)alkoxy; aryl(C₁-C₆)alkoxy-;(C₁-C₆)acyl; (C₁-C₆)alkylamino-; aryl(C₁-C₆)alkylamino-;amino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy-CO—NH—; (C₁-C₆)alkylamino-CO—;(C₂-C₆)alkenyl; (C₂-C₆)alkynyl; hydroxy(C₁-C₆)alkyl-;(C₁-C₆)alkoxy(C₁-C₆)alkyl-; (C₁-C₆)acyloxy(C₁-C₆)alkyl-; nitro;cyano(C₁-C₆)alkyl-; halo(C₁-C₆)alkyl-; nitro(C₁-C₆)alkyl-;trifluoromethyl; trifluoromethyl(C₁-C₆)alkyl-; (C₁-C₆)acylamino-;(C₁-C₆)acylamino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)acylamino-;amino(C₁-C₆)acyl-; amino(C₁-C₆)acyl(C₁-C₆)alkyl-;(C₁-C₆)alkylamino(C₁-C₆)acyl-; ((C₁-C₆) alkyl)₂amino(C₁-C₆)acyl-;—CO₂R²; —(C₁-C₆)alkyl-CO₂R², —C(O)N(R²)₂; —(C₁-C₆)alkyl-C(O)N(R²)₂;R²ON═; R²ON═(C₁-C₆)alkyl-; R²ON═CR²(C₁-C₆)alkyl-; —NR²(OR²);—(C₁-C₆)alkyl-NR²(OR²); —C(O)(NR²OR²); —(C₁-C₆)alkyl-C(O)(NR²OR²);—S(O)_(m)R²; wherein each R² is independently selected from hydrogen,(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—, wherein R³ is(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—(C₁-C₆)alkyl-;R⁴R⁵N—C(O)—O—; R⁴R⁵NS(O)₂—; R⁴R⁵NS(O)₂(C₁-C₆)alkyl-; R⁴S(O)₂R⁵N-;R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein m is 0, 1 or 2, and R⁴ and R⁵ are eachindependently selected from hydrogen or (C₁-C₆)alkyl; —C(═NR⁶)(N(R⁴)₂);—(C₁-C₆)alkyl-C(═NR⁶)(N(R⁴)₂) wherein R⁶ represents OR² or R² wherein R²is defined as above; —OC(O)aryl(C₁-C₆)alkyl; —NH(C₁-C₆)alkyl;aryl(C₁-C₆)alkyl-HN—; and a ketal.
 2. The compound of claim 1 having thestructure of formula (5a)

wherein Q and W are as defined above, and n is 0, 1, 2, or
 3. 3. Thecompound of claim 2, having the structure of formula (5b) or (5c)

wherein Q and W are as defined above.
 4. The compound of claim 1, havingthe structure of formula (5d)

wherein Q, W and Z are as defined above, and n is 0, 1, 2, or
 3. 5. Thecompound of claim 4, having the structure of formula (5e) or (5f),

where Q, W and Z are as defined above.
 6. The compound of claim 1,having the structure of formula (5g),

wherein Q, W and Z are as defined above, and n is 0, 1, 2, or
 3. 7. Thecompound of claim 6, having the structure of formula (5h) or (5i),

wherein Q, W and each Z are as defined above.
 8. The compound of claim1, wherein Q is bromo, iodo or chloro.
 9. The compound of claim 1,wherein Q is bromo.